The epigenetics of CHARGE syndrome

Abstract

In biology, we continue to appreciate the fact that the DNA sequence alone falls short when attempting to explain the intricate inheritance patterns for complex traits. This is particularly true for human disorders that appear to have simple genetic causes. The study of epigenetics, and the increased access to the epigenetic profiles of different tissues has begun to shed light on the genetic complexity of many basic biological processes, both physiological and pathological. Epigenetics refers to heritable changes in gene expression that are not due to alterations in the DNA sequence. Various mechanisms of epigenetic regulation exist, including DNA methylation and histone modification. The identification, and increased understanding of key players and mechanisms of epigenetic regulation have begun to provide significant insight into the underlying origins of various human genetic disorders. One such disorder is CHARGE syndrome (OMIM 214800), which is a leading cause of deaf-blindness worldwide. A majority of CHARGE syndrome cases are caused by haploinsufficiency for the CHD7 gene, which encodes an ATP-dependent chromatin remodeling protein involved in the epigenetic regulation of gene expression. The CHD7 protein has been highly conserved throughout evolution, and research into the function of CHD7 homologs in multiple model systems has increased our understanding of this family of proteins, and epigenetic mechanisms in general. Here we provide a review of CHARGE syndrome, and discuss the epigenetic functions of CHD7 in humans and CHD7 homologs in model organisms.

Keywords

Drosophila / Kismet / CHD7 / CHARGE syndrome / chromatin remodeling

References

[1] Aalfs J D, Kingston R E (2000). What does ʻchromatin remodelingʼ mean? Trends Biochem Sci, 25(11): 548–555

[2] Allen M D, Religa T L, Freund S M, Bycroft M (2007). Solution structure of the BRK domains from CHD7. J Mol Biol, 371(5): 1135–1140

[3] Allis C D, Berger S L, Cote J, Dent S, Jenuwien T, Kouzarides T, Pillus L, Reinberg D, Shi Y, Shiekhattar R, Shilatifard A, Workman J, Zhang Y (2007). New nomenclature for chromatin-modifying enzymes. Cell, 131(4): 633–636

[4] Bajpai R, Chen D A, Rada-Iglesias A, Zhang J, Xiong Y, Helms J, Chang C P, Zhao Y, Swigut T, Wysocka J (2010). CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature, 463(7283): 958–962

[5] Balasubramanian D, Akhtar-Zaidi B, Song L, Bartels C F, Veigl M, Beard L, Myeroff L, Guda K, Lutterbaugh J, Willis J, Crawford G E, Markowitz S D, Scacheri P C (2012). H3K4me3 inversely correlates with DNA methylation at a large class of non-CpG-island-containing start sites. Genome Med, 4(5): 47

[6] Balow S A, Pierce L X, Zentner G E, Conrad P A, Davis S, Sabaawy H E, McDermott B MJr, Scacheri P C (2013). Knockdown of fbxl10/kdm2bb rescues chd7 morphant phenotype in a zebrafish model of CHARGE syndrome. Dev Biol, 382(1): 57–69

[7] Basson M A, van Ravenswaaij-Arts C (2015). Functional Insights into Chromatin remodelling from studies on CHARGE syndrome. Trends Genet, 31(10): 600–611

[8] Blake K D, Hartshorne T S, Lawand C, Dailor A N, Thelin J W (2008). Cranial nerve manifestations in CHARGE syndrome. Am J Med Genet A, 146A(5): 585–592

[9] Blake K D, Prasad C (2006). CHARGE syndrome. Orphanet J Rare Dis, 1(1): 34

[10] Bosman E A, Penn A C, Ambrose J C, Kettleborough R, Stemple D L, Steel K P (2005). Multiple mutations in mouse Chd7 provide models for CHARGE syndrome. Hum Mol Genet, 14(22): 3463–3476

[11] Bouazoune K, Kingston R E (2012). Chromatin remodeling by the CHD7 protein is impaired by mutations that cause human developmental disorders. Proc Natl Acad Sci USA, 109(47): 19238–19243

[12] Boyer L A, Latek R R, Peterson C L (2004). The SANT domain: a unique histone-tail-binding module? Nat Rev Mol Cell Biol, 5(2): 158–163

[13] Cavalli G, Paro R (1999). Epigenetic inheritance of active chromatin after removal of the main transactivator. Science, 286(5441): 955–958

[14] Daubresse G, Deuring R, Moore L, Papoulas O, Zakrajsek I, Waldrip W R, Scott M P, Kennison J A, Tamkun J W (1999). The Drosophila kismet gene is related to chromatin-remodeling factors and is required for both segmentation and segment identity. Development, 126(6): 1175–1187

[15] de Lonlay-Debeney P, Cormier-Daire V, Amiel J, Abadie V, Odent S, Paupe A, Couderc S, Tellier A L, Bonnet D, Prieur M, Vekemans M, Munnich A, Lyonnet S (1997). Features of DiGeorge syndrome and CHARGE association in five patients. J Med Genet, 34(12): 986–989

[16] Dorighi K M, Tamkun J W (2013). The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to counteract Polycomb group repression in Drosophila. Development, 140(20): 4182–4192

[17] Engelen E, Akinci U, Bryne J C, Hou J, Gontan C, Moen M, Szumska D, Kockx C, van Ijcken W, Dekkers D H, Demmers J, Rijkers E J, Bhattacharya S, Philipsen S, Pevny L H, Grosveld F G, Rottier R J, Lenhard B, Poot R A (2011). Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. Nat Genet, 43(6): 607–611

[18] Fasulo B, Deuring R, Murawska M, Gause M, Dorighi K M, Schaaf C A, Dorsett D, Brehm A, Tamkun J W (2012). The Drosophila MI-2 chromatin-remodeling factor regulates higher-order chromatin structure and cohesin dynamics in vivo. PLoS Genet, 8(8): e1002878

[19] Feng W, Khan M A, Bellvis P, Zhu Z, Bernhardt O, Herold-Mende C, Liu H K (2013). The chromatin remodeler CHD7 regulates adult neurogenesis via activation of SoxC transcription factors. Cell Stem Cell, 13(1): 62–72

[20] Feng W, Liu H K (2013). Epigenetic regulation of neuronal fate determination: the role of CHD7. Cell Cycle, 12(24): 3707–3708

[21] Fraga M F, Ballestar E, Paz M F, Ropero S, Setien F, Ballestar M L, Heine-Suner D, Cigudosa J C, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector T D, Wu Y Z, Plass C, Esteller M (2005). Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA, 102(30): 10604–10609

[22] Gangaraju V K, Bartholomew B (2007). Mechanisms of ATP dependent chromatin remodeling. Mutat Res, 618(1–2): 3–17

[23] Gao X, Gordon D, Zhang D, Browne R, Helms C, Gillum J, Weber S, Devroy S, Swaney S, Dobbs M, Morcuende J, Sheffield V, Lovett M, Bowcock A, Herring J, Wise C (2007). CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis. Am J Hum Genet, 80(5): 957–965

[24] Ghosh R, Vegesna S, Safi R, Bao H, Zhang B, Marenda D R, Liebl F L (2014). Kismet positively regulates glutamate receptor localization and synaptic transmission at the Drosophila neuromuscular junction. PLoS ONE, 9(11): e113494

[25] Gregory L C, Gevers E F, Baker J, Kasia T, Chong K, Josifova D J, Caimari M, Bilan F, McCabe M J, Dattani M T (2013). Structural pituitary abnormalities associated with CHARGE syndrome. J Clin Endocrinol Metab, 98(4): E737–E743

[26] He D, Marie C, Zhao C, Kim B, Wang J, Deng Y, Clavairoly A, Frah M, Wang H, He X, Hmidan H, Jones B V, Witte D, Zalc B, Zhou X, Choo D I, Martin D M, Parras C, Lu Q R (2016). Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination. Nat Neurosci, doi: 10.1038/nn.4258

[27] Hurd E A, Adams M E, Layman W S, Swiderski D L, Beyer L A, Halsey K E, Benson J M, Gong T W, Dolan D F, Raphael Y, Martin D M (2011). Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome. Hear Res, 282(1–2): 184–195

[28] Hurd E A, Capers P L, Blauwkamp M N, Adams M E, Raphael Y, Poucher H K, Martin D M (2007). Loss of Chd7 function in gene-trapped reporter mice is embryonic lethal and associated with severe defects in multiple developing tissues. Mamm Genome, 18(2): 94–104

[29] Hurd E A, Micucci J A, Reamer E N, Martin D M (2012). Delayed fusion and altered gene expression contribute to semicircular canal defects in Chd7 deficient mice. Mech Dev, 129(9–12): 308–323

[30] Hurd E A, Poucher H K, Cheng K, Raphael Y, Martin D M (2010). The ATP-dependent chromatin remodeling enzyme CHD7 regulates pro-neural gene expression and neurogenesis in the inner ear. Development, 137(18): 3139–3150

[31] Jacobs-McDaniels N L, Albertson R C (2011). Chd7 plays a critical role in controlling left-right symmetry during zebrafish somitogenesis. Dev Dyn, 240(10): 2272–2280

[32] Janssen N, Bergman J E, Swertz M A, Tranebjaerg L, Lodahl M, Schoots J, Hofstra R M, van Ravenswaaij-Arts C M, Hoefsloot L H (2012). Mutation update on the CHD7 gene involved in CHARGE syndrome. Hum Mutat, 33(8): 1149–1160

[33] Jongmans M C, Admiraal R J, van der Donk K P, Vissers L E, Baas A F, Kapusta L, van Hagen J M, Donnai D, de Ravel T J, Veltman J A, Geurts van Kessel A, De Vries B B, Brunner H G, Hoefsloot L H, van Ravenswaaij C M (2006). CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet, 43(4): 306–314

[34] Jongmans M C, Hoefsloot L H, van der Donk K P, Admiraal R J, Magee A, van de Laar I, Hendriks Y, Verheij J B, Walpole I, Brunner H G, van Ravenswaaij C M (2008). Familial CHARGE syndrome and the CHD7 gene: a recurrent missense mutation, intrafamilial recurrence and variability. Am J Med Genet A, 146A(1): 43–50

[35] Kaminsky Z A, Tang T, Wang S C, Ptak C, Oh G H, Wong A H, Feldcamp L A, Virtanen C, Halfvarson J, Tysk C, McRae A F, Visscher P M, Montgomery G W, Gottesman I I, Martin N G, Petronis A (2009). DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet, 41(2): 240–245

[36] Kim K H, Roberts C W (2013). CHD7 in charge of neurogenesis. Cell Stem Cell, 13(1): 1–2

[37] Kirmizis A, Santos-Rosa H, Penkett C J, Singer M A, Vermeulen M, Mann M, Bahler J, Green R D, Kouzarides T (2007). Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation. Nature, 449(7164): 928–932

[38] Kita Y, Nishiyama M, Nakayama K I (2012). Identification of CHD7S as a novel splicing variant of CHD7 with functions similar and antagonistic to those of the full-length CHD7L. Genes Cells, 17(7): 536–547

[39] Kornberg R D, Lorch Y (1999). Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell, 98(3): 285–294

[40] Kosaki K (2011). Role of rare cases in deciphering the mechanisms of congenital anomalies: CHARGE syndrome research. Congenit Anom (Kyoto), 51(1): 12–15

[41] Kouzarides T (2007). Chromatin modifications and their function. Cell, 128(4): 693–705

[42] Kouzarides T (2007). SnapShot: Histone-modifying enzymes. Cell, 131(4): 822–822.e1

[43] Kouzarides T (2007). SnapShot: Histone-modifying enzymes. Cell, 128(4): 802

[44] Lalani S R, Safiullah A M, Fernbach S D, Harutyunyan K G, Thaller C, Peterson L E, McPherson J D, Gibbs R A, White L D, Hefner M, Davenport S L, Graham J MJr, Bacino C A, Glass N L, Towbin J A, Craigen W J, Neish S R, Lin A E, Belmont J W (2006). Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. Am J Hum Genet, 78(2): 303–314

[45] Layman W S, Hurd E A, Martin D M (2011). Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome. Hum Mol Genet, 20(16): 3138–3150

[46] Layman W S, McEwen D P, Beyer L A, Lalani S R, Fernbach S D, Oh E, Swaroop A, Hegg C C, Raphael Y, Martens J R, Martin D M (2009). Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome. Hum Mol Genet, 18(11): 1909–1923

[47] Melicharek D, Shah A, DiStefano G, Gangemi A J, Orapallo A, Vrailas-Mortimer A D, Marenda D R (2008). Identification of novel regulators of atonal expression in the developing Drosophila retina. Genetics, 180(4): 2095–2110

[48] Melicharek D J, Ramirez L C, Singh S, Thompson R, Marenda D R (2010). Kismet/CHD7 regulates axon morphology, memory and locomotion in a Drosophila model of CHARGE syndrome. Hum Mol Genet, 19(21): 4253–4264

[49] Micucci J A, Layman W S, Hurd E A, Sperry E D, Frank S F, Durham M A, Swiderski D L, Skidmore J M, Scacheri P C, Raphael Y, Martin D M (2014). CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome. Hum Mol Genet, 23(2): 434–448

[50] Mueller-Planitz F, Klinker H, Ludwigsen J, Becker P B (2013). The ATPase domain of ISWI is an autonomous nucleosome remodeling machine. Nat Struct Mol Biol, 20(1): 82–89

[51] Papp B, Muller J (2006). Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins. Genes Dev, 20(15): 2041–2054

[52] Paro R, Strutt H, Cavalli G (1998). Heritable chromatin states induced by the Polycomb and trithorax group genes. Novartis Found Symp, 214: 51–61; discussion 61–56, 104–113

[53] Patten S A, Jacobs-McDaniels N L, Zaouter C, Drapeau P, Albertson R C, Moldovan F (2012). Role of Chd7 in zebrafish: a model for CHARGE syndrome. PLoS ONE, 7(2): e31650

[54] Petruk S, Sedkov Y, Johnston D M, Hodgson J W, Black K L, Kovermann S K, Beck S, Canaani E, Brock H W, Mazo A (2012). TrxG and PcG proteins but not methylated histones remain associated with DNA through replication. Cell, 150(5): 922–933

[55] Pinto G, Abadie V, Mesnage R, Blustajn J, Cabrol S, Amiel J, Hertz-Pannier L, Bertrand A M, Lyonnet S, Rappaport R, Netchine I (2005). CHARGE syndrome includes hypogonadotropic hypogonadism and abnormal olfactory bulb development. J Clin Endocrinol Metab, 90(10): 5621–5626

[56] Reisman D, Glaros S, Thompson E A (2009). The SWI/SNF complex and cancer. Oncogene, 28(14): 1653–1668

[57] Richmond T J, Davey C A (2003). The structure of DNA in the nucleosome core. Nature, 423(6936): 145–150

[58] Sanlaville D, Verloes A (2007). CHARGE syndrome: an update. Eur J Hum Genet, 15(4): 389–399

[59] Santoro R, Li J, Grummt I (2002). The nucleolar remodeling complex NoRC mediates heterochromatin formation and silencing of ribosomal gene transcription. Nat Genet, 32(3): 393–396

[60] Schnetz M P, Bartels C F, Shastri K, Balasubramanian D, Zentner G E, Balaji R, Zhang X, Song L, Wang Z, Laframboise T, Crawford G E, Scacheri P C (2009). Genomic distribution of CHD7 on chromatin tracks H3K4 methylation patterns. Genome Res, 19(4): 590–601

[61] Schnetz M P, Handoko L, Akhtar-Zaidi B, Bartels C F, Pereira C F, Fisher A G, Adams D J, Flicek P, Crawford G E, Laframboise T, Tesar P, Wei C L, Scacheri P C (2010). CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression. PLoS Genet, 6(7): e1001023

[62] Souriau J, Gimenes M, Blouin C, Benbrik I, Benbrik E, Churakowskyi A, Churakowskyi B (2005). CHARGE syndrome: developmental and behavioral data. Am J Med Genet A, 133A(3): 278–281

[63] Srinivasan S, Armstrong J A, Deuring R, Dahlsveen I K, McNeill H, Tamkun J W (2005). The Drosophila trithorax group protein Kismet facilitates an early step in transcriptional elongation by RNA Polymerase II. Development, 132(7): 1623–1635

[64] Srinivasan S, Dorighi K M, Tamkun J W (2008). Drosophila Kismet regulates histone H3 lysine 27 methylation and early elongation by RNA polymerase II. PLoS Genet, 4(10): e1000217

[65] Tellier A L, Cormier-Daire V, Abadie V, Amiel J, Sigaudy S, Bonnet D, de Lonlay-Debeney P, Morrisseau-Durand M P, Hubert P, Michel J L, Jan D, Dollfus H, Baumann C, Labrune P, Lacombe D, Philip N, LeMerrer M, Briard M L, Munnich A, Lyonnet S (1998). CHARGE syndrome: report of 47 cases and review. Am J Med Genet, 76(5): 402–409

[66] Terriente-Felix A, Molnar C, Gomez-Skarmeta J L, de Celis J F (2011). A conserved function of the chromatin ATPase Kismet in the regulation of hedgehog expression. Dev Biol, 350(2): 382–392

[67] Therrien M, Morrison D K, Wong A M, Rubin G M (2000). A genetic screen for modifiers of a kinase suppressor of Ras-dependent rough eye phenotype in Drosophila. Genetics, 156(3): 1231–1242

[68] Torres-Padilla M E, Parfitt D E, Kouzarides T, Zernicka-Goetz M (2007). Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature, 445(7124): 214–218

[69] Vissers L E, van Ravenswaaij C M, Admiraal R, Hurst J A, de Vries B B, Janssen I M, van der Vliet W A, Huys E H, de Jong P J, Hamel B C, Schoenmakers E F, Brunner H G, Veltman J A, van Kessel A G (2004). Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet, 36(9): 955–957

[70] Workman J L (2006). Nucleosome displacement in transcription. Genes Dev, 20(15): 2009–2017

[71] Zentner G E, Hurd E A, Schnetz M P, Handoko L, Wang C, Wang Z, Wei C, Tesar P J, Hatzoglou M, Martin D M, Scacheri P C (2010a). CHD7 functions in the nucleolus as a positive regulator of ribosomal RNA biogenesis. Hum Mol Genet, 19(18): 3491–3501

[72] Zentner G E, Layman W S, Martin D M, Scacheri P C (2010b). Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome. Am J Med Genet A, 152A(3): 674–686

Acknowledgments

We would like to thank Edward A. Waddell and Dr. Faith Liebl for critical reading of the manuscript, the CHARGE syndrome Foundation, and members of the CHARGE syndrome Foundation scientific advisory board for their work on CHARGE. Work in the Marenda laboratory is supported by a grant from the National Science Foundation (IOS 1256114) to DRM.

Nina Latcheva, Rupa Ghosh, and Daniel Marenda declare that they have no conflict of interest.

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